Naturally-occurring DNA intercalating antibiotics are complex molecules that typically contain a multiring aglycone portion such as an anthracycline that is linked to one or more glycosides that themselves can be linked to one or more additional glycosidic rings or other structures. Exemplary of such antibiotics are daunorubicin (daunomycin), doxorubicin, (adriamycin), the bleomycins, plicamycin (mithramycin), the esperamicins and the calicheamicins.
Oligosaccharide-containing antibiotics also exist that further contain a single aromatic ring compound. One such antibiotic is lasacoid A, which forms lipid soluble complexes with divalent calcium ions as well as with essential amines such as catecholamines.
The glycoside-containing portion of such molecules is typically a substituted oligosaccharide. The oligosaccharide often itself contains relatively unusual sugar components such as daunosamine in the case of daunorubicin and doxorubicin, and L-gulose and 3-O-carbamoyl-D-mannose for the bleomycins.
The oligosaccharide portions of the esperamicins and the calicheamicins are still more complex, with both molecules containing four glycosidic units and a substituted benzene moiety. The glycosidic units of both esperamicins and calicheamicins include one sulfur substituent-containing glycoside unit, one N-ethylamine substituent-containing glycoside unit and one glycoside unit that contains a glycosidic bond formed by linkage through the oxygen atom of a hydroxylamine substituent group whose nitrogen atom is bonded to the ring of the sulfur substituent-containing glycoside.
Laboratory syntheses of antibiotics such as those discussed before can be carried out by separate formation of the multiring or single ring aglycone and oligosaccharide portions of the molecules, followed by linking of the two portions to form the complete antibiotic, or by adding glycoside units one or more at a time to the multiring aglycone portion and then to each other. Such syntheses are usually arduous not only because the aglycone components are often difficult to prepare, but also because the oligosaccharide portions are also difficultly made, typically containing relatively unusual glycosidic units, and because each glycosidic linkage must be formed stereospecifically.
Thus, for the oligosaccharide portions, contrary to the recent advances in the step-wise syntheses of polypeptides and oligonucleotides, there have heretofore neither been techniques nor reagents available whereby the synthetic chemist could readily prepare a desired oligosaccharide in a relatively routine manner. Recent advances in the step-wise syntheses of oligosaccharide and other poly- or oligoglycosidic molecules have been reported by Danishefsky and co-workers [(a) Halcomb et al., J. Am. Chem. Soc., 111:6661 (1989); and (b) Friesen et al., J. Am. Chem. Soc., 111:6656 (1989)] who reported that a number of glycosidic units could be linked in a step-wise manner not dissimilar to a step-wise polypeptide synthesis to prepare glycosidic compounds having predetermined, stereo-controlled glycosidic linkages.
Those reported advances utilized substituted glycal compounds as key intermediates in the stereo-controlled glycosidic bond formation reactions. Unfortunately, not all glycals that would otherwise be suitable for a step-wise synthesis are readily available; i.e., the glycals are known or can be prepared, but are prepared with relative difficulty. This is particularly the case for glycals that are derivatives of the gulal and allal series of compounds, a gulal derivative being present in lasacoid A as well as being present in the sulfur substituent-containing glycoside present in the esperamicins and the calicheamicins.
It would therefore be beneficial if substituted gulal and allal compounds could be prepared so that such compounds could be used as intermediates in the preparation of lasacoid A, an esperamicin and/or a calicheamicin or a derivative thereof. The disclosure that follows describes a high yield synthetic procedure whereby such substituted gulal and allal compounds can be prepared.